Posttranslational Regulation of eNOS by Estrogen in the Vagina and Clitoris

阴道和阴蒂雌激素对 eNOS 的翻译后调节

• 批准号: 7074436
• 负责人: BILJANA MUSICKI
• 金额: $ 24.52万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7074436
• 关键词: age difference; aging; arousal; biological signal transduction; caveolins; endocrine disorder; estrogens; female; female reproductive system; fluorimetry; guanine nucleotide binding protein; heat shock proteins; hormone regulation /control mechanism; hormone therapy; immunocytochemistry; immunoprecipitation; laboratory rat; nitric oxide synthase; ovariectomy; phosphatidylinositol 3 kinase; phosphorylation; posttranslational modifications; protein protein interaction; sex behavior disorder; age difference; aging; arousal; biological signal transduction; caveolins; endocrine disorder; estrogens; female; female reproductive system; fluorimetry; guanine nucleotide binding protein; heat shock proteins; hormone regulation /control mechanism; hormone therapy; immunocytochemistry; immunoprecipitation; laboratory rat; nitric oxide synthase; ovariectomy; phosphatidylinositol 3 kinase; phosphorylation; posttranslational modifications; protein protein interaction; sex behavior disorder

DESCRIPTION (provided by applicant): Female sexual arousal disorder (FSAD) is a major component of female sexual dysfunctions in general, affecting 25-70% of women. The mechanisms for FSAD are poorly understood. Aging and hormonal influences are widely associated with FSAD. Estrogen primarily is believed to contribute to the control of genital blood flow during the sexual response. However, the molecular mechanisms of sex steroid hormone, and specifically estrogen action in vascular physiological processes, including that of the genital vasculature, are poorly understood. Vascular effects of estrogen are attributed to its regulation of endothelial nitric oxide synthase (eNOS), yet the physiological role of nitric oxide (NO) and the molecular mechanisms of eNOS regulation by estrogen in the female genital tract are largely unknown. In vitro studies have shown that the increase in endothelial NO production does not necessarily require an increase in eNOS abundance; it may result from specific posttranslational modification of eNOS. The overall goal of the proposal is to investigate the mechanisms of estrogen regulation of eNOS in the female genital tract. We will first evaluate whether estrogen stimulates eNOS phosphorylation through PI3K/Akt-dependent mechanisms, influences eNOS interactions with regulatory protens (increases its interaction with the heat shock protein-90 and decreases its interaction with caveolin-1), and affects the counterregulatory balance between eNOS and the RhoA/Rho- kinase signaling pathway (inhibits the RhoA/Rho-kinase contraction pathway) in female genital tract vasculature. This hypothesis will be tested in adult short-term ovariectomized rats after acute estrogen treatment to determine the effect of estrogen on eNOS regulatory function independent of eNOS gene regulation. Next we will evaluate whether these mechanisms of eNOS posttranslational modification are impaired by chronic estrogen deficiency in the context of aging, and whether early versus delayed long-term estrogen administration may preserve eNOS and endothelial function. This hypothesis will be tested in intact, ovariectomized, and ovariectomized estrogen-treated adult, middle-aged, and aged rats. The proposed study applies to the understanding and treatment of female sexual arousal disorder by elucidating novel mechanisms of vascular effects of estrogen. At the same time it may advance treatments for multiple disease states associated with endothelial dysfunction and alterations in hormonal milieu.

描述（由申请人提供）：女性性唤醒疾病（FSAD）通常是女性性功能障碍的主要组成部分，影响了25-70％的女性。 FSAD的机制知之甚少。衰老和激素的影响与FSAD广泛相关。雌激素主要据信在性反应期间有助于控制生殖器血流。然而，对性类固醇激素的分子机制，在包括生殖器脉管系统的血管生理过程中特别是雌激素作用的理解很差。雌激素的血管作用归因于其对内皮一氧化氮合酶（eNOS）的调节，但一氧化氮（NO）的生理作用以及雌激素在女性生殖道中调节eNOS调节的分子机制在很大程度上尚不清楚。体外研究表明，内皮的增加无产生不一定需要增加eNOS丰度。它可能是由eNOS的特定翻译后修饰引起的。该提案的总体目标是研究女性生殖道中eNOS的雌激素调节机制。我们将首先评估雌激素是否通过PI3K/AKT依赖性机制刺激eNOS磷酸化，从而影响eNOS与调节蛋白的相互作用（增加了其与热休克蛋白90的相互作用，并减少了其与Caveolin-1的相互作用，并影响了eNOS与eNOS和eNOS的eNASE FATION PATION（ENOS）的相互作用（女性生殖道脉管系统中的Rhoa/Rho-kinase收缩途径）。急性雌激素治疗后，将在成年的短期卵巢卵巢切除大鼠中检验该假设，以确定雌激素对eNOS调节功能的影响，而不是eNOS基因调节。接下来，我们将评估这些eNOS翻译后修饰的这些机制是否因衰老的慢性雌激素缺乏症受到损害，以及早期和延迟的长期雌激素给药是否可以保留eNOS和内皮功能。该假设将以完整，卵巢切除和卵巢切除的雌激素治疗的成人，中年和老年大鼠进行检验。拟议的研究适用于通过阐明雌激素血管作用的新机制来理解和治疗女性性唤醒疾病。同时，它可能会推进对与内皮功能障碍和激素环境改变相关的多种疾病状态的治疗。